On the basis of findings at this Institute that: (a) several 2 feet-fluoro-5-substitute ara-C nucleosides designed and synthesized under this grant exhibited exceptionally marked and selective antiherpetic activity, both in vitro and in vivo; (b) one of these nucleosides, FIAC, underwent Phase I and II clinical trials and proved to be superior to ara-A for the treatment of Herpes zoster infections in immunosuppressed cancer patients, and (c) another nucleoside, FMAU, exhibited even more potent activity against Herpes simplex type 1 in infected mice and also demonstrated significant activity against ara-C resistant leukemias in mice, development of practical syntheses of selected representatives of 5 classes of nucleosides structurally related to the lead compounds FIAC and FMAU will be undertaken. In view of our findings that certain of our 5-substituted xylosyl nucleosides bearing good leaving groups on C-3 feet show exceptionally potent activity in vitro and, since such compounds may undergo neighboring group displacement reactions in vivo to liberate area-C type nucleoside (acting as masked precursors) or may be active in their own right, we will synthesize selected representatives of two classes of xylosyl-pyrimidines structurally related to these xylosyl lead nucleosides as potential antiviral and/or anticancer agents. "In-house" antiviral, biochemical and chemotherapeutic collaborative studies for proper evaluation of nucleosides of all seven classes to be synthesized are described. These studies should lead to the development of new agents superior to those drugs currently available for the treatment of cancer and certain viral diseases in man.